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| ID | Type | Description | Link |
|---|---|---|---|
| FRGS/1/2022/SKK01/UPM/02/4 | Other Grant/Funding Number | Ministry of Higher Education, Malaysia |
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| Name | Class |
|---|---|
| University of Oxford | OTHER |
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Transcranial magnetic stimulation is a medical device that can alter motor cortical (M1) excitability through the scalp via various protocols. Among these, intermittent- and continuous-theta burst stimulation (iTBS/cTBS) are increasingly used protocols to enhance or suppress M1 excitability, respectively, beyond stimulation. However, the poor reproducibility and high inter-individual variability in responses to TBS protocols are matters of concern. This study will explore whether ketone monoester supplementation can boost TBS efficacy via their mechanistic convergence on Brain-Derived Neurotrophic Factor (BDNF).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| KME then placebo supplement with iTBS stimulation | Experimental | KME drink with iTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a placebo drink with iTBS stimulation over the left M1 hand region |
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| Placebo then KME supplement with iTBS stimulation | Experimental | Placebo drink with iTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a KME drink with iTBS stimulation over the left M1 hand region |
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| KME then placebo supplement with cTBS stimulation | Experimental | KME drink with cTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a placebo drink with cTBS stimulation over the left M1 hand region |
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| Placebo then KME supplement with cTBS stimulation | Experimental | Placebo drink with cTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a KME drink with cTBS stimulation over the left M1 hand region |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketone Monoester (KME) | Dietary Supplement | 500 mg/kg body weight of the KME supplement |
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| Measure | Description | Time Frame |
|---|---|---|
| Motor evoked potential (MEP) | Peak-to-peak MEP amplitude elicited by single-pulse TMS over the left M1 representation of the first dorsal interosseous (FDI) muscle. In each MEP measurement, 12 MEP readings will be collected, elicited by single-pulse TMS at an intensity of 120% resting motor threshold and separated by 15 seconds. In each timepoint post-TBS, the mean value of MEPs (aka, conditioned MEPs) will be averaged and compared to pre-TBS (aka, baseline MEPs) using the following equation: (conditioned MEP amplitude/baseline MEP amplitude) × 100. A value of 90-110 represents no change, while values < 90% represent suppression and > 110% facilitation of the M1 plasticity following TBS. | Pre-TBS (baseline) and post-TBS at 0, 5, 10, 20, and 30 minutes. |
| Measure | Description | Time Frame |
|---|---|---|
| TMSens_Q questionnaire | Self-reported side effects using the TMSens_Q questionnaire to evaluate the tolerability of the KME-TBS combination. | At 30 minutes post-TBS stimulation |
| Corticospinal excitability indices |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Wan Aliaa Wan Sulaiman, FRCP | Universiti Putra Malaysia | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Sultan Abdul Aziz Shah | Serdang | Selangor | 43400 | Malaysia |
Deidentified raw datasets collected during the trial will be freely available upon completion on the Open Science Framework repository at https://osf.io/
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This is a partial crossover study.
The study protocol involves two interventions administered sequentially during each visit:
Supplement intervention (KME/placebo) followed after one hour by a stimulation intervention (iTBS/cTBS).
There will be two separate groups of subjects undergoing different TBS protocols (iTBS vs cTBS).
The subjects of each group will crossover the supplement intervention (KME and placebo) in two visits separated by one week.
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| Placebo | Dietary Supplement | Taste-matched placebo drink |
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| iTBS | Device | iTBS stimulation will be applied using a butterfly figure-of-eight Cool-B70 coil connected to a MagPro R30 stimulator with add-on Theta Burst option (MagVenture A/S, Farum, Denmark). |
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| cTBS | Device | cTBS stimulation will be applied using a butterfly figure-of-eight Cool-B70 coil connected to a MagPro R30 stimulator with add-on Theta Burst option (MagVenture A/S, Farum, Denmark). |
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Resting motor threshold (RMT) followed by motor-evoked potential at 120% RMT intensity
| Pre-KME supplementation and at 1 hour post-KME supplementation |
| Blood pressure | Systolic blood pressure (SBP), Diastolic Blood Pressure (DBP), and Mean Arterial Pressure (MAP) using fully automated oscillometric sphygmomanometer | Pre-supplementation, at 1 hour post-supplementation/pre-TBS stimulation, and serially thereafter every 3-5 minutes until 30 minutes post-TBS |
| Heart rate | Heart rate (bpm) using pulse oximeter | Pre-supplementation, at 1 hour post-supplementation/pre-TBS stimulation, and continuously thereafter for 30 minutes post-TBS |
| Blood glucose | On-site using a portable glucometer | Pre-KME supplementation and at 30 minutes post-TBS stimulation |
| Blood beta-hydroxybutyrate | On-site using a portable glucometer | Pre-KME supplementation and at 30 minutes post-TBS stimulation |
| Serum brain-derived neurotrophic factor | Serum levels of mature brain-derived neurotrophic factor (mBDNF) and pro-BDNF isoforms | Pre-KME supplementation and at 30 minutes post-TBS stimulation |
| BDNF genetic polymorphism | BDNF rs6265 single nucleotide polymorphism | At the baseline (pre-KME supplementation) |